JPH05239104A - Total or partial ester of gellan and composition and material containing the same - Google Patents

Abstract

In the total and partial esters of gellan, the esterifying alcohol component is derived from aliphatic, araliphatic, cycloaliphatic or heterocyclic alcohols ; and salts of said partial esters are obtained with inorganic or organic bases. A pharmaceutical preparation contains, as an active ingredient, an effective amount of a gellan ester or one of its salts as defined, or one of its salts together with a pharmaceutically acceptable excipient. The total or partial ester of gellan or a salt thereof is used in ophthalmology, dermatology, otolaryngology, dentistry, angiology, obstetrics or neurology.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ester of gellan in which all or part of the carboxy group of gellan is esterified, and a pharmacologically acceptable salt of the partial ester with a metal or an organic base.

The compound retains useful and valuable gelling, bioplastic and pharmaceutical properties and can be used in many fields, from cosmetics to surgical products, pharmaceuticals and foods. The present invention also includes pharmaceutical preparations containing as an active ingredient one or more of the above gellan esters or salts thereof.

Furthermore, the present invention relates to (1) full and partial esters of gellan, which are themselves pharmacologically active substances or are combined with pharmacologically active substances; and (2) The present invention relates to a medicament containing a carrier containing a full or partial ester.

[0004]

Gellan is an extracellular microbial polysaccharide produced from the Pseudomonas elodea cell line and has the following structural formula: -3) -β-D-glcp- (1-4) -β-D- glcpA- (1-4) -β-D-glcp- (1-
4) -α-L-rhamp- (1- [wherein, glcp is glucose, glcpA is D-glucuronic acid, and rhamp is rhamnose]] and is composed of repeating tetrasaccharide units. In its native form, gellan contains an O-acetyl group at the C (6) position of the first glcp residue and an O-glyceric group at the C (2) position of the same residue. A viscous solution is formed which can form a weak and thermolabile gel after addition of salts, especially salts of divalent cations such as Ca ²⁺ and Mg ²⁺ .

Due to the deacylation of natural gellan,
A good gelling agent (“Gerlite”) is obtained which is commercially available for incorporation in the food sector. In the presence of an aqueous solution of MgCl ₂ or CaCl ₂ (about 0.1% w / v salt and 0.8-1% w / v polysaccharide) Gerlite produces a highly resistant gel which is autoclaved. Stable and thermoreversible when treated with. They are chemically inert and usually resistant to enzymatic degradation. Gellan is used industrially because of its biocompatibility and because of the special properties mentioned above. Moreover, this latter is significantly dependent on the charge density and hydration of the polysaccharide chains and on the nature of the counterion, according to the results of detailed physicochemical studies. Therefore, altering the above essential parameters by partial esterification of the carboxy group along the gellan chain would have a large impact on the physicochemical behavior of the derivative (ester) both in situ and in solution. Is predicted. Similarly, the nature and extent of interactions between the derivative and various synthetic and natural species (including proteins) will be largely influenced by the chemistry of the ester moiety and the degree of esterification. Is predicted.

In order to produce gellan esters with industrial potential, this method of esterification is mild (avoiding as many chain breaks as possible) and the final degree of esterification and yield It is important that the point be easily controllable. A simple and convenient way to meet the above requirements embraced by the invention is to treat the quaternary ammonium of gellan with a conventional alkylating agent in an organic solvent, preferably a solvent such as aprotic methylsulfoxide. On the basis of the production of gellan ester. This process makes it possible to obtain a wide variety of gellan esters, including mixed esters, especially esters of monohydric n-aliphatic alcohols and esters of arylaliphatic, cycloaliphatic and heterocyclic monohydric alcohols. . The method also allows the esterification of gellan with a suitable dihydric alcohol to give different degrees of cross-linked insoluble derivatives (a function of experimental conditions). However, a central object of the present invention is to provide novel derivatives of gellan in which the uronic acid residues lined up along the polysaccharide chain are esterified with monohydric alcohols, derivatives soluble in water or organic solvents, and the preparation thereof. Is the way to do it.

[0007]

The central object of the present invention is novel whole and partial esters of gellan, and the process for their preparation. The invention also relates to the use of this gellan ester in the food, paper, textile, cosmetic and pharmaceutical industries, in medicine and surgery, and in the restoration of art. The invention therefore also comprises novel gellan ester-based articles for use in these various industrial fields, such as foods, cosmetics, pharmaceutical preparations, and biodegradable plastic materials for use in medicine and surgery. Is. The novel esters according to the present invention include all and partial esters of gellan. In partial esters, the non-esterified carboxyl group can be salified with a metal or organic base. These salts, as well as the industrial articles containing them, are part of the invention.

All and partial esters of gellan can be used in various industrial fields in which gellan is already used in its deacetylated form, for example in the fields of medicine, hygiene-surgery, cosmetics and food. it can. It is also possible to use the esters in industrial products and products, for example in cosmetics, hygiene products, surgical products, pharmaceutical products or foods and their additives, in particular emulsifiers, emulsion stabilizers, thickeners and other products. It is a part.

[0009]

With the discovery of the full and partial esters of gellan according to the present invention, new uses for the esters of gellan have also been found. That is, the use as a carrier for pharmaceutically active substances, especially substances having a topical, oral, rectal or ocular effect, and also for parenteral use. The present invention therefore also relates to these novel uses and pharmaceutical preparations which contain the gellan esters according to the invention as carriers for their respective products, preferably active substances.

The gellan ester of the present invention can be used as a carrier for a pharmacologically active substance having an alcohol component which forms an ester bond with gellan. In the pharmaceutical preparations of the invention, therapeutically active alcohols (e.g.,
Of particular interest are pharmaceutical preparations containing esters of gellan derived from any of the alcohols listed below).

The present invention also includes salts of gellan partial esters with metals or organic bases. The term "ester of gellan" or "gellan ester" refers to
It should be understood that it refers to both the ester itself and this salt. In particular, the pharmaceutical preparations with one or more pharmacologically active substances can have a pharmacologically active or inactive gellan ester as a carrier, or basic pharmacologically active substances. Active substances can be used to salify all or part of the free carboxyl groups of the gellan partial ester.

The present invention makes available a group of new products in the industrial and scientific fields mentioned above which answers the need for improved products. The monohydric ester according to the present invention is superior when administered to an organism because the residues of the monohydric alcohol are metabolized in the organism to degradation products without any specific toxicity problems. This means that alcohols containing no toxic substituents,
This is usually the case, especially in the case of esters derived from monohydric aliphatic or cycloaliphatic alcohols and the like. Therefore, this novel ester would be of particular benefit in the food industry for the above reasons.

[0013] Since the toxicity of a large number of gellan monohydric alcohol esters according to the present invention is low,
It can be used in the fields of cosmetics, hygiene-surgery and agricultural foods. In this field, new gellan ester,
It can be used as a biodegradable plastic material having various functions as required as described below. For example, gellan ester can be used for a wide variety of polymeric materials used in hygiene and surgical products (polyurethanes, polyesters, polyolefins, polyamides, polysiloxanes,
It can be used as an additive to vinyl and acrylic polymers) to enhance the biocompatibility of these materials.

In the field of cosmetics and medicine, the gellan esters according to the invention can be used to prepare ointments, creams and other types of agents for topical application, or cosmetics such as sunscreen creams. Here, they act as stabilizers and emulsifiers. In medicine they can be used as binders for tablets or as disintegrants with the same advantages. According to a particularly important aspect of the present invention, gellan esters are useful as carriers for pharmacologically active substances, especially for topical or ocular application. The application of this novel ester can be carried out in different ways, for example as follows: (1) The gellan ester acts as a true carrier, which is physically and possibly mechanically bound to the active substance. (2) the (partial) ester of gellan is salified with the active substance; or (3) the gellan ester is esterified with the alcohol of the active substance.

Combinations of the above may also be used. For example, (1) and (2) or (1) and (3). Further, in (2) and (3), different alcohol residues can be combined in the gellan ester, and the gellan ester salt can have a basic component. Some of the alcohol residues are derived from pharmacologically inactive alcohols,
It is also possible to obtain mixed-type esters, some of which are derived from pharmacologically active alcohols. Similarly, for salts of gellan esters, both therapeutically active organic base residues and inert basic residues such as metal salts can be obtained in the same ester.

In the industrial field, ie, for example, food, paper,
The first group of gellan esters according to the present invention useful in the textile and printing industry, and in the manufacture of hygiene, medical surgery, cleansers, household products and the like, is the group that utilizes the properties of the gellan component. Such esters are derived from aliphatic, arylaliphatic, cycloaliphatic or heterocyclic alcohols which have no toxic or pharmacological effects, for example saturated aliphatic or cycloaliphatic alcohols. Examples of these alcohols will be described later.

The second group of useful gellan esters is a therapeutically useful gellan ester in which the pharmacological properties of the alcohol component are predominant, ie pharmacologically active alcohols such as steroid alcohols and eg cortisone. And an ester of its derivative with gellan. These esters retain properties that are qualitatively similar to those of alcohols, but have a different spectrum of action compared to known esters, and a more balanced and consistent pharmacological profile. It ensures a positive effect and usually exhibits a marked retarding effect.

A third group of gellan esters according to the invention is one in which the carboxy group moiety of gellan is esterified with a pharmaceutically active alcohol and another moiety is not pharmaceutically active or only slightly active. It is an ester that has been esterified with an alcohol. By measuring the percentage of these two types of alcohol as esterifying components, ie by balancing the ratio between the two types of alcohol moieties, they have the same activity as pharmaceutically active alcohols and Owing to the ester groups of the chemically inert acids, gellan esters can be obtained which have increased stability and bioavailability for the desired and characteristic activities of pharmaceutically active alcohols.

The fourth group of esters according to the invention are those in which the ester groups are miscible in that they are derived from two different therapeutically active alcohols.
Again, the ester may be all or part, ie only some of the carboxy groups are derived from two different therapeutically active alcohols, such as cortisone steroids and antibiotics, while , Another group may be free, or may form a salt with, for example, an alkyl metal, especially sodium, or all carboxy groups may be esterified with the alcohol. Also, the carboxy group moiety is esterified with a therapeutically active alcohol, the other moiety is esterified with another therapeutically active alcohol, and the third moiety is esterified with a therapeutically inactive alcohol. , And the fourth moiety may be salted with a metal or a therapeutically active or inactive base, or the ester may be prepared with three or more alcohol components, which may be in the free form. .

The gellan esters mentioned above whose carboxylic acid groups remain free can be salted with metals or organic bases, such as alkali or alkaline earth metals or ammonia or nitrogen organic bases.

The invention further comprises the use of an inert gellan ester of an alcohol for admixture with a therapeutically active substance, in all cases the free carboxy group being inert but therapeutically active. Can be salified (salt formed) with a pharmaceutically acceptable base or a therapeutically active base, and the present invention also includes a pharmaceutical product or pharmaceutical preparation obtained by using the gellan ester thereof.

Thus, the main object of the present invention is to
Provided are all or partial esters of gellan with araliphatic, cycloaliphatic or heterocyclic alcohols, and salts of these partial esters with inorganic or organic bases.

The second object of the present invention is to treat the quaternary ammonium salt of gellan with an esterifying agent in an aprotic solvent and, if desired, the free carboxy group of the partial gellan ester thus obtained. Is formed with an inorganic or organic base to form a gellan ester.

A third object of the present invention is the use of gellan esters as substances for cosmetic application, pharmaceutically active substances, and vehicles for pharmaceutical preparations or medicaments such as: 1 ) A pharmaceutically active substance or with a pharmaceutically active substance, 2) All or partial ester of gellan, or a salt of the partial ester with an inorganic or organic base, or at least one ester group or salt formation A pharmaceutical preparation or vehicle consisting of a pharmaceutical preparation or pharmaceutical product, which is composed of an ester of gellan, whose carboxy group is derived from a therapeutically active alcohol or base, and which may also form salts with inorganic or organic bases.

The aliphatic alcohol used as the esterification component of the carboxy group of the gellan of the present invention includes, for example, 1
To 34 carbon atoms, which may be saturated or unsaturated, and other free functional groups or functionally modified groups such as amino, hydroxy, aldehyde, keto, Mercapto, carboxy groups or groups derived therefrom, such as hydrocarbyl dihydrocarbylamino groups (the term "hydrocarbyl" as used herein refers to, for example, CnH2n + 1 type monovalent hydrocarbon groups as well. , Also means divalent or trivalent groups such as "alkylene" -CnH2n or "alkylidene" -CnH2n), ether or ester groups, acetal or ketal groups, thioether or thioester groups, and esterified carboxy groups or carbamide groups. (carbamidic group) and one or two hydrocarbyl groups, nitrile groups or halogens It may be substituted by a carbamide group substituted by.

Of the above-mentioned groups containing a hydrocarbyl group, lower aliphatic groups having a maximum of 6 carbon atoms such as alkyl are preferable. Such an alcohol may have a heteroatom such as oxygen, nitrogen and sulfur atoms in the carbon chain. Alcohols substituted with one or two of said functional groups are preferred.

Among the alcohols of the above groups in the present invention, alcohols to be preferentially used are 1 to 12,
In particular, those having 1 to 6 carbon atoms, wherein the hydrocarbyl group of amino, ether, ester, thioether, thioester, acetal or ketal group is an alkyl group having 1 to 4 carbon atoms, or an esterified carboxy group or The hydrocarbyl group of the substituted carbamide group may be alkyl having the same number of carbon atoms as the alkyl group, and the amino or carbamide group may be an alkyleneamino or alkylenecarbamide group having 1 to 8 carbon atoms. Among these alcohols, saturated and unsaturated alcohols such as methyl, ethyl, propyl, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl, hexyl, octyl, nonyl and dodecyl alcohol are preferable. .. Particularly preferred is a chain such as n-octyl or n-dodecyl alcohol. Among the substituted alcohols of this group are dihydric alcohols such as ethylene glycol, propylene glycol or butylene glycol; trihydric alcohols such as glycerin; aldehyde alcohols such as tartron alcohol; lactic acid alcohols such as α-oxypropionic acid, glycols. Carboxylic acid alcohols such as acids, malic acid, tartaric acid and citric acid; aminoalcohols such as aminoethanol, aminopropanol and n-aminobutanol, and dimethyl and diethyl derivatives at the amino group, choline, pyrrolidinylethanol, piperidinylethanol. , Piperazinyl ethanol, and n-
Included are the corresponding derivatives of propyl or n-butyl alcohol, monothioethylene glycol or its alkyl derivatives, such as the ethyl derivative at the mercapto group.

Higher saturated aliphatic alcohols include cetyl alcohol and myricyl alcohol. Of particular importance to the purpose of the present invention are:
This is especially the case with higher unsaturated alcohols having one or more double bonds which are related to terpenes such as those found in many essential oils, eg citronellal, geraniol, nerol, nerolidol, linalool. , Farnesol and phytol. Possible lower unsaturated alcohols are allyl alcohol and propargyl alcohol.

Araliphatic alcoh
ols) is one having only one benzene residue, whose aliphatic chain has from 1 to 4 carbon atoms and whose benzene residue has from 1 to 3 methyl, hydroxy or halogen atoms. , Optionally substituted by chlorine, bromine, iodine, and the aliphatic chain is one or more selected from free amino groups or groups formed from mono- or dimethyl groups or pyrrolidine or piperidine groups. It may be substituted by the functional group of. Among these alcohols, benzyl alcohol and phenethyl alcohol are particularly preferable.

The cycloaliphatic or aliphatic cycloaliphatic alcohol can be derived from mono- or polycyclic hydrocarbons, which can have 1 to 34 carbon atoms. Among alcohols derived from cyclic monoanular are rings containing 1 to 12 carbon atoms, preferably 5 to 7 carbon atoms, such as methyl. Optionally substituted by 1 to 3 lower alkyl groups such as ethyl, propyl or isopropyl groups. Specific examples of the alcohol of this group include cyclohexanol, cyclohexanediol, 1,2,3-cyclohexanetriol, and 1,3,5-cyclohexanetriol (phloroglucitol), inositol, and carbomenthol, menthol, Alcohols derived from p-menthane, such as α- and γ-terpineols, 1-terpineols, 4-terpineols and piperitols, or mixtures of these alcohols known as “terpineols”, 1,4
-And 1,8-terpine. Among the alcohols derived from hydrocarbons having fused rings, there are, for example, Tujan, pinane and camphane groups such as Tsujanol, Sabinol, Pinol hydrate, D- and L-borneol and D- and L-isoborneol. There is.

The polycyclic, aliphatic cycloaliphatic alcohols used to obtain the esters according to the invention include sex hormones and their synthetic homologues, in particular sterols such as corticosteroids and their derivatives, cholic acid and I have steroids. For example, cholesterol, dihydrocholesterol, epidihydrocholesterol, coprosterol, epicoprosterol, sitosterol, stigmasterol, ergosterol, cholic acid, deoxycholic acid, lithocholic acid, estriol, estradiol, equilenin, equilin and their alkyl derivatives. And an ethynyl or propynyl derivative at the 17-position, such as 17-ethynyl-estradiol or 7-methyl-17-ethynyl-estradiol,
Pregnenolone, pregnanediol, testosterone, and derivatives thereof, such as 17-methyltestosterone, 1,2-dehydrotestosterone and 17-methyl-1,2-dehydrotestosterone, and alkyl derivatives at the 17-position of testosterone and 1,2-dehydrotestosterone, For example, 17-ethynyl-testosterone, 17-propynyltestosterone, norgestrel, hydroxyprogesterone, corticosterone, deoxycorticosterone, 19-nortestosterone,
19-nor-17-methyltestosterone, and 19-
Nor-17-ethynyltestosterone, cortisone, hydrocortisone, prednisone, prednisolone, fludrocortisone, dexamethasone, betamethasone, parameterzone, flumethasone, fluocinolone, fluprednilidene, clobetasol, beclomethasone, aldosterone, deoxycorticosterone, alfaxolone, alfaxolone, alfaxolone. , Anti-hormonal substances such as bolasterone, and cyproterone.

Also useful as esterifying agents for the esters of the present invention are the cardiac glycosides genin (aglycone) such as digitoxigenin, digoxygenin, digoxigenin, strophantidine, tigogenin and saponins.

Other alcohols which can be used in the present invention are vitamin alcohols such as axerophtal, vitamins D2 and D3, anoylin, lactoflavin, ascorbic acid, riboflavin, thiamine and pantothenic acid.

Useful heterocyclic alcohols include, for example, furfuryl alcohol, alkaloids, and derivatives thereof such as atropine, scopolamine, cinchonine, cinchonidine, quinine, morphine, codeine, nalorphine, N-butylscopolammonium bromide, ajumarin; Phenylethylamine such as ephedrine, isoproterenol, epinephrine; perphenazine, pipothiazine, carphenazine, homophenazine,
Phenothiazine drugs such as acetophenazine, fluphenazine, N-hydroxyethyl-promethazine chloride; thioxanthene drugs such as flupentixar and clopentixal; anticonvulsants such as meprofendiol; psychotic drugs such as opipramol; Antiemetics such as oxypentyl; analgesics such as carbetidine and phenoperidine and metadol; hypnotics such as etodoxidine; anorectic substances such as benzhydrol and difemethoxyzine; minor tranquilizers such as hydroxyzine; cinnamedrin, difilulin, mephenesin , Metacarbamol, chlorphenesin, 2,2-
Muscle relaxants such as diethyl-1,3-propanediol, guaifenesin, idrosylamide; coronary vasodilators such as dipyridamole and oxyfedrine; adrenaline inhibitors such as propananol, timolol, pindolol, buplanolol, atenolol, metoprolol, plactrol. Anticancer drugs such as 6-azauridine, cytarabine, and furoxyuridine; chloramphenicol,
Antibiotics such as thiamphenicol, erythromycin, oleandomycin, lincomycin; antiviral agents such as iodooxyuridine; peripheral vasodilators such as isonicotinyl alcohol; carbonic anhydrase inhibitors such as sulocarbylate; tiaramide etc. Anti-dyspnea and anti-inflammatory drugs; 2-sulfonylanilinoethanol and other sulfonamides.

As mentioned above, it may be possible to use gellan esters, in which the ester group is derived from two or more therapeutically active hydroxy substances, and all possible variants thereof. Particularly useful are those in which there are two different types of ester groups derived from a drug having a hydroxy moiety, the remaining carboxy groups are free, and the metal or one or more of the above bases, if desired. A substance which may have a therapeutic activity in itself, for example, is salted with a base having the same or similar activity as the esterification component. Specifically, the gellan ester can be derived on the one hand from the above-mentioned anti-inflammatory steroids and on the other hand from the above-mentioned vitamins, alkaloids or antibiotics.

The degree of esterification of gellan by the above alcohols depends on the particular properties desired for different areas of application, eg the greater or lesser lipophilicity or hydrophilicity of the particular tissue such as HIF. .. In general, a high degree of esterification of gellan up to total esterification increases its lipophilicity and thus decreases its water solubility. For the therapeutic use of the novel esters of the invention, for example, the degree of ester is adjusted to ensure adequate water solubility, eg, 10 mg / ml, despite being better lipophilic than natural gellan. Should be. Naturally, the effect of the molecular size of the esterification component of its own must be considered. This usually affects water solubility in an inversely proportional manner.

As mentioned above, the esterification of the carboxy group of gellan has various advantages, in different areas, for example in the medical field by the use of therapeutic ester, or by the use of plastic particle ester. For example, it can be used for surgery. Its therapeutic use is as described above, but considering the esterification of therapeutically active alcohols such as anti-inflammatory corticosteroids, gellan should be used as a means to enhance the therapeutic efficacy. You can

Thus, in the context of similar therapeutically active alcohols, gellan functions as a particularly effective vehicle which is perfectly compatible with the biological environment. The alcohols listed above for use in the esterification of the present invention are various pharmaceutically active alcohols, and the corresponding gellan ester indications are characterized by the same as their free alcohols. Further, as described above, in the partial ester with a therapeutically active alcohol, the remaining carboxy group of the gellan component is esterified with a pharmaceutically inactive alcohol such as saturated lower aliphatic alcohol such as ethyl or isopropyl alcohol. Can be converted.

A particularly useful aspect of the present invention is that the drug can be prepared more stably than what has been obtained so far. For example, gellan esters with therapeutically active alcohols, which may be salted with therapeutically active bases, can be used to obtain drugs with a "retarding" effect.

For use in cosmetics, a pharmaceutically inert alcohol, for example a straight-chain or branched chain alcohol of this type having 1 to 8 carbon atoms, as exemplified above, is used. It is preferred to use full or partial esters of gellan with saturated or unsaturated fatty alcohols such as saturated alcohols. Of particular interest are unsaturated alcohols having one or more double bonds, such as, for example, vinyl or allyl alcohols and their condensed derivatives, especially polyhydric alcohols such as polyvinyl alcohol or glycerin, among others. Also in this case, a mixed ester can be used depending on the intended use.

Also useful are cycloaliphatic alcohols derived from, for example, cyclopentane or cyclohexane, and derivatives thereof substituted with lower alkyl of 1 to 4 carbon atoms such as methyl. Of particular interest are cycloaliphatic and terpene-derived aliphatic-cycloaliphatic alcohols, such as those exemplified above, and those obtained from therapeutically active alcohols, and others for use in cosmetics. It can be done.

The alcohols preferably used to produce hygiene and surgical materials are substantially the same as those exemplified above for use in cosmetics. In the esters according to the invention, the percentage of the esterified groups varies greatly depending on the intended use of the product, ie mainly in the various areas of application mentioned above. Therefore, sanitary-surgic
It is preferred to use all or partial esters with a high degree of esterification of, for example, 80% to 100% of the total carboxy groups present, for the preparation of al.

Of particular interest are partial esters in which at least 5% and at most 90% of all carboxy groups in gellan are esterified, of which 50% to 80% percent are food, cosmetic and pharmaceutical products. Can be used particularly preferably in the field of.

It is of course possible to vary the proportion of partial esters with respect to the number of different types of ester groups in the mixed ester, eg in the case of two types of groups:
The ratio is preferably 0.1: 1 to 1: 0.1, which is also the case for all esters. In the case of esters for therapeutic use, the ratio is 0.5: 1 to 1: 0.5
Is preferred. Such a ratio is also effective for all esters, and in the case of partial esters, it is preferable to consider the above percentage with respect to the comprehensive number of esterified groups. In the case of the partial esters of the invention, the non-esterified carboxy groups may remain free or may be salted. The base for forming such salts is selected according to the intended use of the product. Inorganic salts can be formed from alkali metals such as potassium, especially sodium and ammonium, or salts thereof from alkaline earth metals such as calcium, magnesium or aluminum.

Further of particular interest are organic bases,
In particular, it is a salt with an azotized base (nitriding base), and thus a salt with an aliphatic, araliphatic, cycloaliphatic or heterocyclic amine. The ammonium salts described above can be derived from those that are therapeutically active or non-toxic but therapeutically inactive amines. Preferred of the former are aliphatic amines, such as mono-, di- and tri-alkylamines having 1 to 8 carbon atoms, or arylalkylamines, the aliphatic portion of which is the same as above. It is the number of carbon atoms and means a benzene group in which aryl may be substituted with 1 to 3 methyl groups, halogen atoms or hydroxy groups. Biologically inert bases for carrying out salt formation include rings with 4 to 6 carbon atoms which may contain heteroatoms selected from nitrogen, oxygen and sulphur, for example piperazine or morpholine. It may be cyclic, such as containing monocyclic alkyleneamines, or substituted by amino or hydroxy functional groups such as aminoethanol, ethylenediamine, ephedrine or choline.

Quaternary ammonium salts of partial esters, for example tetraalkylammonium salts having the corresponding number of carbon elements, can also be prepared, wherein the fourth alkyl group has 1 to 4 carbon element numbers such as methyl groups. Certain salts of this type are preferred.

The biologically active amines used for salt formation and whose therapeutic activity has already been exploited are all known nitriding basic drugs, which are drugs as described below. Are: alkaloids, peptides, phenothiazines, benzodiazepines, thioxanthenes, hormones, vitamins, anticonvulsants, antipsychotics, antiemetics, analgesics, hypnotics, anorectics, tranquilizers, muscle relaxants, coronary vasodilators, Antitumor drug, antibiotic, antibacterial drug, antiviral drug, antimalarial drug, carbonic anhydrase inhibitor, nonsteroidal anti-inflammatory drug, vasoconstrictor, cholinergic agonist, cholinergic blocker, adrenergic agonist Sex agonists, adrenergic agonists, anesthetic antagonists.

All of the above drugs having a nitriding basic group associated with therapeutically active alcohols or gellan esters, such as those exemplified herein with various antibiotics, are exemplified by particularly useful drugs. Is mentioned.

Salting the partial ester with the therapeutically active base and using that salt is a specific example of a gellan ester acting as a vehicle. This is done by simply adding to the active substance all or partial esters, or one of the therapeutically acceptable but not biologically active substances, especially their salts with alkali metals such as sodium. be able to.

Therefore, the use of gellan esters as vehicles opens up the possibility of application in new pharmaceutical products such as: 1) the pharmaceutically active substances, their related substances or such substances. Mixtures of two or more, and 2) the gellan esters mentioned above or one of their salts, and such pharmaceuticals are further objects of the invention.

The gellan esters which can be used in these medicaments are those in which the esterified alcohol is not pharmaceutically active per se and is, for example, only the abovementioned aliphatic alcohols. However, pharmaceuticals of this type in which the ester is also pharmaceutically active, such as one of the above esters derived from a pharmaceutically active alcohol, are included in the present invention.

In such pharmaceuticals, if a partial ester of gellan is used, it is desirable to salt the remaining carboxy group with a therapeutically neutral inorganic or organic base, especially an alkali metal such as sodium or ammonium. preferable. When the active substance of 1) above or the corresponding related substance of the substance has a basic group such as an antibiotic containing an amino group, and when a partial ester of gellan having a residual free carboxy group is used, a gellan ester A salt is formed between and the basic substance. Of course, the basic substance can be in excess and will have a basic salt. Therefore, the pharmaceutical agent of the present invention includes a partial ester of gellan partially forming a salt with the above-mentioned basic pharmaceutically active substance. If the vehicle material is non-basic, non-esterified carboxy groups can also salt with the therapeutically active base. The use of gellan esters as a vehicle is particularly useful in ophthalmology, where an individual compatibility between the new product and the corneal epithelium is observed, followed by good tolerance without any sensitizing effect. You can recognize the sex.

Furthermore, when the above-mentioned drug is administered as a concentrated solution or solid having viscoelasticity, it is completely transparent and adhesive on the corneal epithelium, and a drug with an excellent "delaying effect" is obtained. Homogeneous and stable film preparations can be formed that guarantee extended bioavailability. Such ophthalmic pharmaceuticals are of particular value in the veterinary field, given the lack of available veterinary preparations containing chemicals for the treatment of the eye. In fact, although preparations for human use are commonly used, they do not always guarantee the action of specific areas of the animal and cannot guarantee the individual condition under which they are treated. For example, infectious keratoconjunctivitis, pink eye or IB
K, mainly when treating infections affecting cows, sheep and goats. The particular etiology will be present in these three animals. For example, in the case of dairy cows, the major microorganisms involved are Moraxella bovis.
[However, it is not possible to exclude other viral sources such as rhinotracheitis virus, mycoplasma, rickettsia and chlamydia in sheep, and rickettsia in goats]. The disease is acute and tends to spread rapidly. That is, in its early stages, it presents with symptoms characterized by blepharospasm and excessive tears, followed by purulent secretions, conjunctivitis and keratitis, sometimes with high fever, decreased appetite and decreased milk production. Many. Corneal damage, which can even lead to corneal perforation at the end of the disease, is particularly severe. The clinical course extends from days to weeks. A wide variety of chemical-based treatments are used, administered by local (often associated with anti-inflammatory steroids) and systemic routes. Examples of this are, for example, tetracyclines such as oxytetracycline, penicines such as siloxacillin and benzylpenicin, sulfonamides, polymyxin B (associated with miconazole and prednisolone), chloramphenicol and tylosin. Despite its simplicity of appearance, topical treatment of diseases remains problematic, one reason for which or other reasons related to ophthalmic preparations available to date is antibiotics or sulfamides. This is because the concentration in tear secretion could not reach the therapeutically effective concentration.

This can be understood in the case of the solution formulation, considering that the above-mentioned animals usually hang their heads. However, this is also true for semisolid pharmaceuticals, i.e. the excipients commonly used in semisolid pharmaceuticals do not have the necessary properties to adhere to the corneal surface, and it is generally Since it does not contain a sufficiently high concentration of active substance, it is not possible to perform complete dispersion (percentage of component dispersion). The disadvantages of such conventional eye drops are Slatter et al., Austr. Vet. J., 1982, 59 (3), 69-72.
Page.

The esters of the present invention overcome these difficulties. By the presence of gellan ester as a vehicle of ophthalmic medicine, it is possible to form an excellent preparation without concentration of components, therefore, homogenization, transparency and adhesion to corneal epithelium can be completely performed, without sensitizing effect, It is possible to obtain a complete vehicle which may also have a retarding effect for the active substance.

It goes without saying that the above-mentioned properties of this novel drug can be used outside the ophthalmological field. That is, they can be applied to dermatological areas and mucous membranes, for example, the condition in which the mouth is affected.

Further, the ester of the present invention can be used as, for example, a suppository, since it has a systemic effect by percutaneous reabsorption. All these applications are applicable in both human and veterinary science. In human medicine, this novel drug is particularly relevant in pediatrics. The present invention individually includes all of these therapeutic applications.

The term active substance of component 1) according to the invention should be taken hereafter to mean also associations of two or three active substances or mixtures thereof. Depending on its use in different therapeutic areas, the component 1) can generally be cataloged. This cataloging first distinguishes between human and veterinary drugs, and then the difference in field of application regarding the organs and tissues to be treated, ophthalmology,
Dermatology, otolaryngology, gynecology, aniology (an
biology), neuroscience, or by identifying any type of pathology of internal organs that can be treated by topical (eg, rectal) application. In one aspect of the invention, the pharmaceutically active substance 1) is a substance for ophthalmic use. According to another criterion, it is necessary to classify pharmaceutically active substances 1) according to their effects, such as anesthetics, analgesics, anti-inflammatory agents, vasoconstrictors,
It can be an antibacterial agent or an antiviral agent. For ophthalmology, miotics, anti-inflammatory agents, wound healing and antibacterial effects can be pointed out. In the present invention, component 1) may be an association of two or more active substances contained in many known drugs.

In ophthalmology, for example, it may be an association of antibiotics, antiphlogistics and vasoconstrictors, or some antibiotics may be accompanied by one or more antiphlogistics, or mydriatics. , Or one or more antibiotics, such as with miotics or wound healing agents or antiallergic agents. For example, the following ophthalmic associations can be used: kanamycin + phenylephrine + dexamethasone phosphate, kanamycin + beta methasone phosphate + phenylephrine, or other antibiotics used in ophthalmology (eg loritetracycline, neomycin, gentamicin, tetracycline, etc.). Similar association.

In the dermatology, as an active ingredient 1), a plurality of different antibiotics (eg, erythromycin, gentamicin, neomycin, gramicidin, polymyxin B) or a combination of the antibiotics and anti-inflammatory agents (eg corticosteroids). Associated with, for example, hydrocortisone + neomycin, hydrocortisone + neomycin + polymyxin B + gramicidin, dexamethasone +
Neomycin, fluorometholone + neomycin, prednisolone + neomycin, triamcinolone + neomycin + gramicidin + nystatin, or other associations used in conventional formulations for dermatology are possible.

The association of different active substances is, of course, not limited to these fields, and in each of the above medical fields the same associations already used in the pharmaceutical formulations known in the art. Can be used.

In the above examples relating to the use of substances 1) which are basic, the salts derived from the gellan partial ester may be salts of different types. That is, all the remaining carboxy groups may be salified, or only a part thereof may be salified to form an ester-acid salt or ester-
Neutral salts may be produced. The number of acid groups left free can be important in preparing a drug with a particular pH. One aspect of the invention is to start with an amorphous solid powdery anhydrous solid state of the salt, which may already be isolated and purified, in a concentrated aqueous gelatinous solution when it comes into contact with the tissue to be treated. It is possible to prepare a drug that constitutes a density that exhibits viscosity and that has elasticity. Since these qualities are maintained even at the time of large dilution, various concentrations of aqueous solution or physiological saline solution can be used instead of the anhydrous salt. Further, other additives or excipients such as other mineral salts may be added to the above solution in order to adjust pH and osmotic pressure of these solutions. Such salts can, of course, also be used in the preparation of gels, inserts, creams or ointments containing other excipients or ingredients used in conventional pharmaceutical formulations.

In a preferred aspect of the invention, a drug containing a gellan ester or a salt thereof with a therapeutically active or inactive substance is used as the sole excipient (with the possible exception of aqueous solvents). is there). Also mixtures obtained from any type of drug described herein,
Mixtures of the drugs are also included in the present invention, and may be a mixture of free gellan and gellan ester or a salt thereof (for example, sodium salt).

Examples of pharmaceutically active substances 1) of the invention for use in ophthalmic drugs are basic and non-basic antibiotics,
Examples include aminoglycosides, macrolides, tetracyclines, and the like, examples of which are gentamicin, neomycin, streptomycin, dihydrostreptomycin, kanamycin, amikacin, tobramycin, spectinomycin, erythromycin, oleandomycin, carbomycin, spiramycin, oxytetracycline. , Lolitetracycline, bacitracin, polymyxin B, gramicidin, colistin, chloramphenicol, lincomycin, vancomycin,
It may be novobiocin, ristocetin, clindamycin, amphotericin B, griseofulvin, nystatin, and their salts (sulfates or nitrates), or mixtures thereof or other active ingredients (for example those mentioned in the following sections). It is a meeting. Other ophthalmic agents that can be effectively used in accordance with the present invention include: other anti-infective agents, such as diethylcarbamazine, mebendazole, sulfamides (sulfacetamide, sulfadiazine, sulfisoxazole, etc.); anti-virus agents and anti-tumor agents. Agents such as iododeoxyuridine, adenine, arabinoside, trifluorothymidine, acyclovir, ethyldeoxyuridine, bromovinyldeoxyuridine, 5-iodo-5'-amino-2 ', 5'-di-
Deoxyuridine, etc .; anti-inflammatory steroids, such as dexamethasone, hydrocortisone, prednisolone, fluoromesolone, medrisone, and salts thereof (such as phosphates); non-steroidal anti-inflammatory agents, such as indomethacin, oxyphenbutazone, flurbiprofen Etc .; Wound healing agents such as epidermal growth factor EGF; Local anesthetics such as benoxynate, proparacaine (their salts may be used); Pilocarpine, methacholine, carbamylcholine, aceclidine, physostigmine, neostigmine, demepotassium and choline such salts Agonists; cholinergic blockers such as atropine and its salts; adrenergic agonists such as noradrenaline, adrenaline, naphazoline, methoxamine (these salts may be used) Marianist; propanolol, timolol, pindolol, bupranolol, atenolol, metoprolol, oxprenolol, practolol,
Adrenergic blockers such as butoxamine, sotalol, butesulin, labetalol and salts thereof.

Mixtures or associations of such agents and mixtures or associations with other active ingredients can also be used as component 1) of the present invention. When an active substance association as described above is used instead of a single active substance 1), the salt of a basic active substance with a partial ester of gellan is a mixed salt of one or more such basic substances. Or it may be a mixed salt of this type having a certain number of other acid groups of the above-mentioned metal or base salified polysaccharides. For example, a pharmaceutically inert alcohol (eg, a low alkanol), a proportion of acid groups salified with the antibiotic kanamycin, another proportion of acid groups salified with the vasoconstrictor phenylephrine, and the remaining proportion of acid groups. Salts of gellan partial esters having a free acid group (which may be salified with, for example, sodium or one of the other metals mentioned above) can be prepared. It is also possible to mix this type of mixed salt with free gellan or a fraction thereof or metal salts thereof, as already indicated for the drug constituted by the salt of the polysaccharide ester and the single active substance.

Examples of active substances used alone or in association with other active ingredients in the dermatology are anti-infective agents, antibiotics, antibacterial agents, anti-inflammatory agents, cell growth inhibitors. Drugs, cytotoxic agents, antiviral agents, therapeutic agents such as anesthetics, and preventive agents such as sunscreens, deodorants, antiseptics, and antiseptics. Examples of antibiotics are erythromycin, bacitracin, gentamicin, neomycin, aureomycin, gramicidin and their associations. Notable examples of antibacterial and antiseptic agents are nitrofurazone, mafenide, chlorhexidine, derivatives of 8-hydroxyquinoline, and salts thereof; notable examples of anti-inflammatory agents are corticosteroids such as prednisolone, dexamethasone, Flumethasone, clobetasol, triamcinolone, acetonide, beta methasone, or salts thereof, such as valerianate, benzoate, dipropionate; fluorouracil,
Cytotoxic drugs such as methotrexate and podophyllin; anesthetics such as dibucaine, lidocaine and benzocaine. These lists only provide examples and all other reagents described in the literature can be used. From the examples given for ophthalmology and dermatology, preparations for intradermal or transmucosal (for example rectal or intranasal) (eg nasal sprays) or preparations for inhalation into the oral cavity or pharynx can be used Medical fields (eg otolaryngology,
It is possible to estimate which drug of the present invention should be used in dentistry, internal medicine such as endocrinology).

Such formulations include, for example, anti-inflammatory agents, vasoconstrictors, pressor agents already mentioned for ophthalmology, vitamins, the abovementioned antibiotics, hormones, chemotherapeutic agents, antibacterial agents mentioned above for dermatology. And so on.

The drug of the present invention may be a solid, for example, a lyophilized powder containing only two components as a mixture or individually encapsulated.

Upon contact with the epithelium to be treated, these solid drugs form solutions of varying concentrations according to the nature of the particular epithelium, exhibiting the same characteristics as solutions previously prepared in vitro. Pre-prepared in-house solutions are another particularly important aspect of the invention. Such solutions are preferably prepared in distilled water or in sterile physiological solution and preferably contain no other pharmaceutical excipients other than gellan ester or one of its salts. The concentration of such solutions can also be varied over a wide range, for example separately for each of the two components or in the range of 0.01-75% for their mixtures or salts. A solution having the above-mentioned viscoelasticity, for example, a solution containing the drug or each component thereof in an amount of 10 to 90% is particularly preferable.

This type of drug is particularly important in either anhydrous form (freeze-dried powder), concentrated aqueous solution, concentrated physiological saline solution, or diluted aqueous solution or diluted physiological saline solution. Mineral salts, which act as
Alternatively, auxiliary substances such as other ophthalmic substances may be added.

To be selected in each case from the drugs according to the invention are those which have an acidity suitable for the environment in which they are applied, ie drugs which have a physiologically tolerable pH. For example, the pH of the salt of the basic active substance and the gellan partial ester depends on the amount of polysaccharide, the amount of salt,
And it can be adjusted by appropriately adjusting the amount of the basic substance itself.

Therefore, for example, when the acidity of the salt of the gellan partial ester and the basic substance is too high, an excess amount of the free acid group is added to the above-mentioned inorganic base (for example, sodium hydrate, potassium hydrate, ammonium hydrate). Etc.).

As a novel and inventive method of the present invention, starting from a quaternary ammonium salt of gellan and an esterifying agent,
Preferably, aprotic organic solvents such as dialkyl sulfoxides and dialkyl carboxylamides, for example, lower alkyl dialkyl sulfoxides, especially of lower fatty acids, especially dimethyl sulfoxide, and lower alkyl dialkylamides of lower fatty acids (eg, dimethylformamide, diethylformamide). , Dimethylacetamide,
Gellan ester can be prepared in diethylacetamide).

However, other aprotic solvents such as alcohols, ethers, ketones, esters, especially aliphatic alcohols, heterocyclic alcohols, and low-boiling ketones such as hexafluoroisopropanol and trifluoroethanol should also be considered. Is. The reaction is preferably carried out in the temperature range of about 0-100 ° C, particularly in the range of about 25-75 ° C, for example about 30 ° C. The esterification is preferably carried out by gradually adding the esterifying agent to the ammonium salt dissolved in one of the abovementioned solvents (eg dimethylsulfoxide).

As alkylating agents, those mentioned above can be used, in particular hydrocarbyl halides, for example alkyl halides. As starting quaternary ammonium salt, it is preferred to use a lower tetraalkylated product of an alkyl group, preferably having 1 to 6 carbon atoms. First and foremost, use tetrabutylammonium gellan. These quaternary ammonium salts can be prepared by reacting a metal salt of gellan, preferably one of the above, especially the sodium or potassium salts, with a sulfonic acid resin salified with a quaternary ammonium base in aqueous solution. . The tetraalkylammonium salt of gellan can be preserved by freeze-drying the eluate.

Since such salts have been modified to be readily soluble in the aprotic solvents mentioned above, esterification of gellan by the method described above is particularly easy and gives a quantitative yield. Therefore, only by this method can the number of carboxyl groups to be esterified of gellan be precisely controlled.

A variation on the method previously described is that potassium or sodium salt of gellan suspended in a suitable solvent such as dimethylsulfoxide is present in the presence of a catalytic amount of a quaternary ammonium salt (eg tetrabutylammonium iodide). Below by reacting with a suitable alkylating agent. Gellans of any origin can be used to prepare the novel esters of the present invention.

In the partial ester of the present invention, all the carboxyl groups remaining in the partial ester of the present invention can be salified by controlling the amount of base so as to obtain a desired stoichiometric salinity. Alternatively, only a part of it can be salified. By accurately measuring salinity, it is possible to obtain esters which have a wide range of dissociation constants and therefore give the desired pH in solution or in therapeutic systems in the system.

Another object of the present invention is to provide a gellan ester as defined above, or a drug obtained by association of such an ester with a pharmaceutically active substance as defined above (ie gellan ester is an agent for an active substance). A pharmaceutical preparation containing one or more of a drug functioning as a dosage form).

The pharmaceutical formulation containing the therapeutically active gellan ester (components 1) and 2) may be provided in the form of said medicament, which contains conventional excipients for oral use, It can be for rectal, parenteral, subcutaneous, topical or intradermal use.

The formulation may be solid or semi-solid, eg pills, tablets, gelatin capsules, capsules, suppositories, soft gelatin capsules and the like. For parenteral and subcutaneous administration, preparations for intramuscular or intradermal administration, or preparations for infusion or intravenous injection may be used and they are therefore suitable for such use. It may be prepared as an active compound solution for mixing with one or more pharmaceutically acceptable excipients or diluents which are osmotically compatible with physiological body fluids or as a lyophilized powder of the active compound. it can. Formulations in the form of sprays, such as nasal sprays, creams or ointments for topical use, or bandages with special treatment for intradermal administration should be considered for topical use. .

The formulations of the present invention can be administered to humans or animals. These formulations preferably contain 0.01% to 10% active ingredient in solutions, sprays, ointments, creams; in solid formulations 1% to 100% active ingredient, preferably It preferably contains from 5% to 50% active ingredient. The dosage will depend on the individual need, intended effect and route of administration chosen. The daily dose of such a formulation can be calculated based on the values used for the known formulation for the corresponding treatment with the therapeutically active alcohol. Thus, for example, the dosage of gellan ester associated with cortisone can be determined from the content of the steroid and the dosage normally administered when it is included in a known pharmaceutical formulation.

One form of pharmaceutical preparation is the drug, for example by association with a gellan ester and the active substance for topical use. It can be in solid form, for example as a lyophilized powder containing only two components 1) and 2) as a mixture or individually encapsulated. Such solid drugs are
Upon contact with the epithelium to be treated, it forms solutions of varying concentrations depending on the nature of the epithelium, and exhibits the same characteristics as the solution formulation, which is also an important aspect of the invention pre-prepared in the laboratory. Such solutions are preferably distilled aqueous solutions or sterile physiological solutions and preferably do not contain any pharmaceutical excipient other than gellan ester or one of its salts. The concentration of such solutions can also vary greatly. For example, the two components can be in concentrations of 0.01% to 75%, either individually or as a mixture or salt. It has the above-mentioned viscoelasticity, for example, 10 to 9
A solution containing 0% of the drug or each of its components is particularly preferable.

Anhydrous forms (lyophilized powders), or solutions, concentrated or diluted in water or physiological solution are the most important of this class of drugs. In addition, an auxiliary substance, particularly an ophthalmic disinfectant, or a mineral salt acting as a buffer solution, or another substance may be added to these drugs.
Of the drugs of the invention, the one to be selected in each case is one which has an acidity suitable for the environment in which it is to be applied, ie a physiologically tolerable pH. For example, the pH of the salt of gellan ester and the basic active substance can be adjusted by appropriately adjusting the amount of the polysaccharide in the salt, the amount of the salt, and the amount of the basic substance itself. Thus, for example, if the acidity of the salt of gellan ester with a basic substance is too high, excess free acid groups are neutralized with the above-mentioned inorganic bases (eg sodium hydrate, potassium hydrate, ammonium hydrate, etc.). To do.

The salts according to the invention are prepared in known manner from solutions, aqueous suspensions or organic solvents in two components 1) and 2) and optionally in specified amounts of the abovementioned alkali metals or alkaline earth metals, or magnesium, It can be prepared by contacting with an aluminum salt or a basic salt and isolating the anhydrous amorphous form salt by known techniques. First of all, a binary component 1) which releases said component from an aqueous solution of the salts of binary components 1) and 2), for example by suitable ion exchange.
And 2) are prepared in an aqueous solution at low temperature (eg 0-20
C.) and store the two solutions at room temperature and freeze-dry the salt thus obtained if it dissolves easily in water, or centrifuge, filter or decant it if it does not dissolve well. After separation, it can be dried. The dosages of these associated drugs are also based on the values when the active ingredient is used alone and can therefore be readily determined by the expert, taking into account the recommended dosages for the corresponding known agents.

In the cosmetics according to the invention, the gellan ester and its salts are mixed with the excipients customarily used in the art, such as those mentioned above for the pharmaceutical formulations. The most commonly used are creams, ointments, lotions for topical use, in which the gellan ester or one of its salts may constitute the active cosmetic ingredient, and also cosmetics such as steroids. Other active ingredients (eg pregnenolone or one of the active ingredients mentioned above)
One) may be added. In such formulations, the gellan ester may be an ester with a cosmetic alcohol (eg dexapanthenol) or an ester with no cosmetic effect (eg a lower aliphatic alcohol as described above). This effect is due to the inherent cosmetic properties of the polysaccharide component, as is the case with free gellan or its salts. However, these cosmetics contain various other active ingredients such as disinfectants, sunscreens,
It may be based on waterproofing agents, rejuvenating agents, anti-wrinkle substances, fragrance substances, especially perfumes and the like. In this case, the gellan ester itself may be the active ingredient, or the gellan ester may be derived from an alcohol having such properties, such as higher aliphatic alcohols or terpene alcohols in the case of perfume, and the gellan ester is It also acts as an excipient associated with them for substances having the properties of Therefore, cosmetic compositions similar to the above-mentioned drugs, in which the pharmaceutically active ingredient 1) is replaced by cosmetic factors and their respective salts, are of particular importance. The use of alcohol-derived esters in the perfume industry is an important technological advance. This is because it allows a slow, constant and long lasting release of aroma components.

One of the important applications of the invention relates to the hygiene and surgical products already mentioned, their method of manufacture and their use. Therefore, the present invention is similar to the gellan products already on the market, but contains all hygiene products, such as inserts or ophthalmic lenses, which contain gellan ester or one of its salts instead of one of its free acid or one of its salts. Etc. are included.

The surgical and hygiene articles of the present invention are represented by gellan esters regenerated from suitable organic solvents and the like. They can be made into mesh sheets, non-mesh sheets, and fibrous forms, and thus as a skin supplement and replacement in cases of severe skin defects (eg burns) or as sutures during surgery. Films, sheets or fibers can be obtained for use in surgery or for hygiene products. The invention is particularly directed to the use of such products and one suitable organic solvent of gellan ester or salt thereof, such as a ketone,
(Ester) forming process in solution. Aprotic solvents such as amides of carboxylic acids, especially dialkylamides or fatty acids of 1 to 5 carbon atoms,
Derived from alkyl groups of 1 to 6 carbon atoms. The organic solvent may also be an organic sulfoxide, i.e. a dialkyl sulfoxide with an alkyl group of 1 to 6 carbon atoms, such as dimethylsulfoxide or diethylsulfoxide. Further, the organic solvent may be a low boiling point fluorinated solvent such as hexafluoroisopropanol. Then, the obtained solution is subjected to a spinning or rolling step and brought into contact with another organic solvent or an aqueous solvent (particularly a lower aliphatic alcohol such as ethyl alcohol (wet spinning)) which can be mixed with this solvent and in which the gellan ester is insoluble. To remove the organic solvent. If a solvent having a sufficiently low boiling point is used for the preparation of the gellan derivative solution, the solvent can be removed in a dry state by a gas flow (heated nitrogen is particularly suitable (dry spinning)). Good results can also be obtained by dry-wet spinning.

The fibers obtained with gellan esters can be used in the manufacture of gauze for use in wound healing or surgery. The use of such gauze offers significant advantages in that they are biodegradable within the organ. Organs, when using a gellan ester derived from a therapeutically acceptable alcohol (eg ethanol),
It contains an enzyme that decomposes the ester into gellan and the corresponding alcohol. Therefore, these gauze and said fibers can be left in the organ after surgery, which are slowly resorbed after the above-mentioned degradation.

In the production of the hygiene and surgical articles mentioned above, the addition of suitable plasticizing substances in order to improve their mechanical characteristics (for example in the case of fibers to improve their resistance to kink). You can Such a plasticizer can be, for example, an alkali salt of a fatty acid (eg, sodium stearate, sodium palmitate), an ester of a high carbon number organic acid, or the like.

Other applications of the new esters, which take advantage of the biodegradability of the esterase enzymes present in organs, are:
The manufacture of capsules for the subcutaneous implantation of drugs, or the manufacture of microcapsules for injection, eg by the subcutaneous or intramuscular route.

All the problems associated with the use of microcapsules in the past and limiting their use
The manufacture of gellan ester-containing microcapsules, which is excluded for the reasons mentioned above, is also very important. This process opens the door widely to applications where delayed effects after injection are desired.

Another medical-surgical application of gellan esters is in the manufacture of a wide variety of solid inserts such as plates, discs, sheets. These are metal or synthetic plastic materials currently in use and are an alternative to those intended to be removed after a period of time.
Formulations made of proteinaceous animal collagen often cause undesired side effects such as inflammation and rejection. In the case of gellan ester this risk does not exist.

Applications in the medical-surgical field of the gellan esters according to the invention also include the production of expandable materials, in particular in the form of sponges, for the treatment of various wounds or traumas.

The present invention also includes the following improvements to the method for producing the novel ester and its salt. That is, it is a production method interrupted at any stage, a production method starting from an intermediate compound and performing the remaining steps, or a production method in which a starting product is produced in the system.

The present invention is illustrated by the following examples, but the present invention is not limited thereto. Guerlain is Kelco March (San Diego, California)
Available from.

Example 1 Preparation of the tetrabutylammonium salt of gellan polysaccharide. Equivalent to 1.27 meq. 8
50 mg dry gellan (sodium salt) with distilled water (700 ml)
Dissolves in. The solution is passed through a column containing a strongly acidic ion exchange resin of the tetrabutylammonium type (50 ml). The eluate is neutralized with tetrabutylammonium hydroxide, then filtered and lyophilized. Yield: 990mg

Example 2 Preparation of (Partial) Ester Containing 60% Carboxyl Group of n-Propyl Ester Type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Propyl iodide (0.146 g, 0.84 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. Distilled water is used to convert the remaining salified carboxyl groups from the tetrabutylammonium form to the tetramethylammonium form.
Tetramethylammonium chloride (16 ml) dissolved in (8 ml)
5 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate was separated by filtration and washed with acetone (2
Wash 3 times with 0 ml) and then dry under vacuum. Yield: 460 mg The degree of esterification of gellan was quantified by IR and NMR spectroscopy. Furthermore, the quantitative determination of the ester group is "Qua
ntitative organic analysis via functional groups ",
1 of 4th Edition, John Wiley and Sons Publication
The saponification method described on pages 69 to 172 is used.

Example 3 Preparation of (partial) ester containing 17% of carboxyl groups of n-propyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Propyl iodide (41.5 mg, 0.24 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. Distilled water is used to convert the remaining salified carboxyl groups from the tetrabutylammonium form to the tetramethylammonium form.
Tetramethylammonium chloride (16 ml) dissolved in (8 ml)
5 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate was separated by filtration and washed with acetone (2
Wash 3 times with 0 ml) and then dry under vacuum. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 4 Preparation of (partial) ester containing 10% of carboxyl group of n-propyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Propyl iodide (24.4 mg, 0.14 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. Distilled water is used to convert the remaining salified carboxyl groups from the tetrabutylammonium form to the tetramethylammonium form.
Tetramethylammonium chloride (16 ml) dissolved in (8 ml)
5 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate was separated by filtration and washed with acetone (2
Wash 3 times with 0 ml) and then dry under vacuum. Yield: 462 mg Quantification of the degree of esterification of gellan was carried out by IR and NMR spectroscopy. Furthermore, the quantitative determination of the ester group is "Qua
ntitative organic analysis via functional groups ",
1 of 4th Edition, John Wiley and Sons Publication
The saponification method described on pages 69 to 172 was used.

Example 5 Preparation of (Partial) Ester Containing 5% of Carboxyl Groups of n-Propyl Ester Type Gellan tetrabutylammonium salt (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Propyl iodide (12.2 mg, 0.07 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. Distilled water is used to convert the remaining salified carboxyl groups from the tetrabutylammonium form to the tetramethylammonium form.
Tetramethylammonium chloride (16 ml) dissolved in (8 ml)
5 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate was separated by filtration and washed with acetone (2
Wash 3 times with 0 ml) and then dry under vacuum. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 6 Preparation of (partial) ester containing 60% of carboxyl groups of ethyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Ethyl iodide (0.131 g, 0.84 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining salified carboxyl groups from tetrabutylammonium type to tetramethylammonium type, distilled water (8 m
tetramethylammonium chloride (165 mg) dissolved in l)
Add. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is isolated by filtration, washed 3 times with acetone (20 ml) then dried in vacuo. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 7 Preparation of (partial) ester containing 17% of carboxyl groups of ethyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Ethyl iodide (37.4 mg, 0.24 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining salified carboxyl groups from tetrabutylammonium type to tetramethylammonium type, distilled water (8 m
tetramethylammonium chloride (165 mg) dissolved in l)
Add. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is isolated by filtration, washed 3 times with acetone (20 ml) then dried in vacuo. Yield: 450 mg Quantification of the degree of esterification of gellan is carried out by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 8 Preparation of (partial) ester containing 10% of carboxyl group of ethyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Ethyl iodide (21.8 mg, 0.14 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining salified carboxyl groups from tetrabutylammonium type to tetramethylammonium type, distilled water (8 m
tetramethylammonium chloride (165 mg) dissolved in l)
Add. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is isolated by filtration, washed 3 times with acetone (20 ml) then dried in vacuo. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 9 Preparation of (partial) ester containing 5% of carboxyl group of ethyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Ethyl iodide (10.9 mg, 0.07 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining salified carboxyl groups from tetrabutylammonium type to tetramethylammonium type, distilled water (8 m
tetramethylammonium chloride (165 mg) dissolved in l)
Add. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is isolated by filtration, washed 3 times with acetone (20 ml) then dried in vacuo. Yield: 470 mg Quantification of the degree of esterification of gellan is carried out by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 10 Preparation of (partial) ester containing 60% of benzyl ester type carboxyl groups Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Benzyl bromide (0.143 g, 0.84 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining salified carboxyl groups from tetrabutylammonium type to tetramethylammonium type, distilled water (8 m
tetramethylammonium chloride (165 mg) dissolved in l)
Add. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is isolated by filtration, washed 3 times with acetone (20 ml) then dried in vacuo. Yield: 460 mg The degree of esterification of gellan was quantified by IR and NMR spectroscopy. Furthermore, the quantitative determination of the ester group is "Qua
ntitative organic analysis via functional groups ",
1 of 4th Edition, John Wiley and Sons Publication
The saponification method described on pages 69 to 172 is used.

Example 11 Preparation of (partial) ester containing 60% of carboxyl group of benzyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Benzyl bromide (41.0 mg, 0.24 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining salified carboxyl groups from tetrabutylammonium type to tetramethylammonium type, distilled water (8 m
tetramethylammonium chloride (165 mg) dissolved in l)
Add. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is isolated by filtration, washed 3 times with acetone (20 ml) then dried in vacuo. Yield: 460 mg The degree of esterification of gellan was quantified by IR and NMR spectroscopy. Furthermore, the quantitative determination of the ester group is "Qua
ntitative organic analysis via functional groups ",
1 of 4th Edition, John Wiley and Sons Publication
The saponification method described on pages 69 to 172 is used.

Example 12 Preparation of (partial) ester containing 10% of benzyl ester type carboxyl group Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Benzyl bromide (23.9 mg, 0.14 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining salified carboxyl groups from tetrabutylammonium type to tetramethylammonium type, distilled water (8 m
tetramethylammonium chloride (165 mg) dissolved in l)
Add. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is isolated by filtration, washed 3 times with acetone (20 ml) then dried in vacuo. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 13 Preparation of (partial) ester containing 5% of carboxyl group of benzyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Benzyl bromide (17.0 mg, 0.07 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining salified carboxyl groups from tetrabutylammonium type to tetramethylammonium type, distilled water (8 m
tetramethylammonium chloride (165 mg) dissolved in l)
Add. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is isolated by filtration, washed 3 times with acetone (20 ml) then dried in vacuo. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 14 Preparation of (partial) ester containing 60% of carboxyl groups of isopropyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Isopropyl iodide (0.146 g, 0.84 meq) is added.
The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining chlorinated carboxyl group from tetrabutylammonium type to tetramethylammonium type, tetramethylammonium chloride (1 ml) dissolved in distilled water (8 ml) was used.
65 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is separated by filtration and the acetone
Wash 3 times (20 ml) then vacuum dry. Yield: 460 mg The degree of esterification of gellan was quantified by IR and NMR spectroscopy. Furthermore, the quantitative determination of the ester group is "Qua
ntitative organic analysis via functional groups ",
1 of 4th Edition, John Wiley and Sons Publication
The saponification method described on pages 69 to 172 is used.

Example 15 Preparation of a (partial) ester containing 17% of isopropyl ester type carboxyl groups Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Isopropyl iodide (41.5 mg, 0.24 meq) is added.
The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining chlorinated carboxyl group from tetrabutylammonium type to tetramethylammonium type, tetramethylammonium chloride (1 ml) dissolved in distilled water (8 ml) was used.
65 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is separated by filtration and the acetone
Wash 3 times (20 ml) then vacuum dry. Yield: 460 mg The degree of esterification of gellan was quantified by IR and NMR spectroscopy. Furthermore, the quantitative determination of the ester group is "Qua
ntitative organic analysis via functional groups ",
1 of 4th Edition, John Wiley and Sons Publication
The saponification method described on pages 69 to 172 is used.

Example 16 Preparation of (partial) ester containing 10% of carboxyl group of isopropyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Isopropyl iodide (24.4 mg, 0.14 meq) is added.
The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining chlorinated carboxyl group from tetrabutylammonium type to tetramethylammonium type, tetramethylammonium chloride (1 ml) dissolved in distilled water (8 ml) was used.
65 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is separated by filtration and the acetone
Wash 3 times (20 ml) then vacuum dry. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 17 Preparation of (partial) ester containing 5% of carboxyl group of isopropyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. Isopropyl iodide (12.2 mg, 0.07 meq) is added.
The solution is shaken well at 30 ° C. for 16 hours. In order to convert the remaining chlorinated carboxyl group from tetrabutylammonium type to tetramethylammonium type, tetramethylammonium chloride (1 ml) dissolved in distilled water (8 ml) was used.
65 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate is separated by filtration and the acetone
Wash 3 times (20 ml) then vacuum dry. Yield: 460 mg The degree of esterification of gellan was quantified by IR and NMR spectroscopy. Furthermore, the quantitative determination of the ester group is "Qua
ntitative organic analysis via functional groups ",
1 of 4th Edition, John Wiley and Sons Publication
The saponification method described on pages 69 to 172 is used.

Example 18 Preparation of (partial) ester containing 60% of carboxyl group of t-butyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. T-Butyl iodide (0.154 g, 0.84 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. Distilled water is used to convert the remaining salified carboxyl groups from the tetrabutylammonium form to the tetramethylammonium form.
Tetramethylammonium chloride (16 ml) dissolved in (8 ml)
5 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate was separated by filtration and washed with acetone (2
Wash 3 times with 0 ml) and then dry under vacuum. Yield: 460 mg The degree of esterification of gellan was quantified by IR and NMR spectroscopy. Furthermore, the quantitative determination of the ester group is "Qua
ntitative organic analysis via functional groups ",
1 of 4th Edition, John Wiley and Sons Publication
The saponification method described on pages 69 to 172 is used.

Example 19 Preparation of (partial) ester containing 17% of t-butyl ester type carboxyl groups Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. T-Butyl iodide (44.1 mg, 0.24 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. Distilled water is used to convert the remaining salified carboxyl groups from the tetrabutylammonium form to the tetramethylammonium form.
Tetramethylammonium chloride (16 ml) dissolved in (8 ml)
5 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate was separated by filtration and washed with acetone (2
Wash 3 times with 0 ml) and then dry under vacuum. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 20 Preparation of (partial) ester containing 10% of carboxyl group of t-butyl ester type Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. T-Butyl iodide (25.7 mg, 0.14 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. Distilled water is used to convert the remaining salified carboxyl groups from the tetrabutylammonium form to the tetramethylammonium form.
Tetramethylammonium chloride (16 ml) dissolved in (8 ml)
5 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate was separated by filtration and washed with acetone (2
Wash 3 times with 0 ml) and then dry under vacuum. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 21 Preparation of (partial) ester containing 5% of t-butyl ester type carboxyl group Tetrabutylammonium salt of gellan (665 mg, 0.7)
5 meq) is dissolved in DMSO (30 ml) at 25 ° C. T-Butyl iodide (12.9 mg, 0.07 meq) is added. The solution is shaken well at 30 ° C. for 16 hours. Distilled water is used to convert the remaining salified carboxyl groups from the tetrabutylammonium form to the tetramethylammonium form.
Tetramethylammonium chloride (16 ml) dissolved in (8 ml)
5 mg) is added. The solution is added dropwise to acetone (250 ml) with shaking. The precipitate was separated by filtration and washed with acetone (2
Wash 3 times with 0 ml) and then dry under vacuum. Yield: 460 mg The degree of esterification of gellan is quantified by IR and NMR spectroscopy. In addition, quantitative determination of ester groups
itative organic analysis via functional groups ", 4
16th edition, John Wiley and Sons Publication
The saponification method described on pages 9 to 172 is used.

Example 22 Preparation of methyl ester of gellan Tetrabutylammonium salt of gellan (8.35 g, 9.4)
(meq.) is dissolved in DMSO (400 ml) at 25 ° C. Methyl iodide (1.67 g, 11.8 meq) is added. Solution 3
Shake well at 0 ° C. for 12 hours, then add dropwise to ethyl acetate (or toluene) (3.5 L) with shaking. The precipitate is filtered, washed 4 times with ethyl acetate and then vacuum dried at 30 ° C. for 24 hours. In this way the title compound (5.5 g) is obtained. In addition, the quantification of ester groups is performed using "Quantitativ
e organic analysis via functional groups ", 4th Edi
tion, John Wiley and Sons Publication 169-1
The saponification method described on page 72 is used.

Example 23 Preparation of benzyl ester of gellan Tetrabutylammonium salt of gellan (10 g, 11.3 m
Equivalent) is dissolved in DMSO (400 ml) at 25 ° C. Benzyl bromide (2.4 g, 14.1 meq) and tetrabutylammonium iodide (0.1 g) are added. The solution at 30 ° C for 1
Shake well for 2 hours, then ethyl acetate (or toluene)
(3.5 L) is added dropwise with shaking. The precipitate is filtered, washed 4 times with ethyl acetate and then vacuum dried at 30 ° C. for 24 hours. In this way the title compound (7.5 g) is obtained. In addition, the quantitative determination of ester groups is performed using the "Quantitative orga
nic analysis via functional groups ", 4th Edition,
It is carried out by the saponification method described on pages 169 to 172 of John Wiley and Sons Publication.

Example 24 Preparation of t-butyl ester of gellan Tetrabutylammonium salt of gellan (10 g, 11.3 m
Equivalent) is dissolved in DMSO (400 ml) at 25 ° C. T-Butyl iodide (2.5 g, 14.1 meq) is added. The solution is shaken well at 30 ° C. for 12 hours and then added dropwise to ethyl acetate (or toluene) (3.5 L) with shaking. The precipitate is filtered, washed 4 times with ethyl acetate and then at 30 ° C. for 24 hours.
Vacuum dry for hours. In this way the title compound (7.0 g)
Is obtained. In addition, the quantification of ester groups is performed using "Quantitat
ive organic analysis via functional groups ", 4th E
dition, John Wiley and Sons Publication 169 ~
The saponification method described on page 172 is used.

Example 25 Preparation of isopropyl ester of gellan Tetrabutylammonium salt of gellan (10 g, 11.3 m
Equivalent) is dissolved in DMSO (400 ml) at 25 ° C. Isopropyl iodide (2.4 g, 14.1 meq) is added. The solution is shaken well at 30 ° C. for 12 hours and then added dropwise to ethyl acetate (or toluene) (3.5 L) with shaking. The precipitate is filtered, washed 4 times with ethyl acetate and then 2 at 30 ° C.
Vacuum dry for 4 hours. Thus, the title compound (6.8
g) is obtained. In addition, quantitative determination of ester groups
native organic analysis via functional groups ", 4th
Edition, John Wiley and Sons Publication 169
~ Saponification method described on page 172.

Example 26 Preparation of ethyl ester of gellan Tetrabutylammonium salt of gellan (10 g, 11.3 m
Equivalent) is dissolved in DMSO (400 ml) at 25 ° C. Ethyl iodide (2.2 g, 14.1 meq) is added. 30 solution
Shake well at ℃ for 12 hours, then add dropwise to ethyl acetate (or toluene) (3.5 L) with shaking. The precipitate is filtered, washed 4 times with ethyl acetate and then vacuum dried at 30 ° C. for 24 hours. In this way the title compound (7.0 g) is obtained. In addition, the quantitative determination of ester groups is based on "Quantitative
organic analysis via functional groups ", 4th Editi
on, John Wiley and Sons Publication 169-17
The saponification method described on page 2 is used.

Example 27 Preparation of ester of gellan containing carboxyl group of methylprednisolone ester (C-21) type The tetrabutylammonium salt of gellan (890 mg, 1 meq) is dissolved in DMSO (40 ml) at 25 ° C. 21-Bromo-methylprednisolone (560 mg, 1.25 meq)
Add. The solution is shaken well at 30 ° C. for 12 hours. The solution is added dropwise to acetone (300 ml) with good shaking. The precipitate was separated by filtration and acetone (30 ml)
Wash 3 times with and then vacuum dry. Methylprednisolone is quantified according to British Pharmacopea, 1980, p.224, after mild alkaline hydrolysis with a hydroalcoholic solution of sodium carbonate and extraction with chloroform.

Example 28 Nonwoven Fabric Made from Benzyl Ester of Gellan A nonwoven fabric having a specific weight (200 gr / m ² ) and thickness (1.5 mm) was constructed with the benzyl ester of gellan. The 3 mm long gellan benzyl ester fibers obtained by the spinning process were mixed in a suitable "screw-hopper" to obtain a fine mixture. The mixture of fibers was loaded into a "carding machine" from which a sheet type with a specific weight (200 gr / m ² ) and thickness (1.8 mm) appeared.
When the sheet was treated with a "needle punch machine", it was produced as a non-woven fabric in which the two substances with a specific weight (200 gr / m ² ) and thickness (1.5 mm) were thoroughly mixed with each other. It was

Example 29 Microspheres of benzyl ester of gellan Gellan ester in which all carboxy groups of the polymer are esterified with benzyl alcohol are added to a neutral solvent such as dimethyl sulfoxide at 0.5 to 5% by weight / volume. It dissolves at a range of concentrations, usually 2% w / v. The solution obtained is hereafter referred to as the discontinuous phase. At this point, to produce a mixture of high viscosity containing Arlacel ^R is a non-ionic surfactant concentration of 1% w / v mineral oil in a suitable reactor. This mixture is henceforth referred to as the continuous phase. While maintaining this at a temperature of 25 ° C. and stirring at a rate of 1000 RPM, the discontinuous phase prepared as described above is added thereto. Under these conditions, two-phase emulsification occurs immediately. The ratio of the two phases (discontinuous phase and continuous phase) is about 1 to 16. After stirring for 15 minutes, ethyl acetate is added. This solvent is completely miscible with the two emulsion phases, but it is not the solvent for the polymer. It was found that that volume of extraction solvent was needed to obtain a complete extract of the total volume of emulsion. Stirrer speed to 1400 to 1500 RPM to speed extraction
Set for 0 minutes, then drop to 500 RPM. The suspension thus obtained is kept stirred and pumped with a screw pump through a squeeze filter set at 1 atmospheric pressure. Once this filtration is complete, pump through a filter of n-hexane, a solvent that has a dual activity of "drying" the product and dissolving any residual surfactant that may be present on the surface of the microspheres.
The product is then placed in a suitable container and stored at 4 ° C.
The average particle size is 10 μm. The molecular weight of the polymer constituting the microspheres is about 500,000 to 800,0.
00.

Example 30 Microspheres of benzyl ester of gellan Gellan ester in which 60% of the carboxy groups of the polymer are esterified with benzyl alcohol is added to a neutral solvent such as dimethyl sulfoxide in an amount of 0.5 to 5% by weight / volume. It dissolves at a concentration in the range of, usually 2% w / v. The solution obtained is hereafter referred to as the discontinuous phase. At this point, to produce a mixture of high viscosity containing Arlacel ^R is a non-ionic surfactant concentration of 1% w / v mineral oil in a suitable reactor.
This mixture is henceforth referred to as the continuous phase. This at 25 ℃
The discontinuous phase prepared as above is added to this while maintaining the temperature of 1000 rpm and stirring at a rate of 1000 RPM. Under these conditions, two-phase emulsification occurs immediately. The ratio of the two phases (discontinuous phase and continuous phase) is about 1 to 16. After stirring for 15 minutes, ethyl acetate is added. This solvent is completely miscible with the two emulsion phases, but it is not the solvent for the polymer. It was found that that volume of extraction solvent was needed to obtain a complete extract of the total volume of emulsion. Agitation speed of 1400 to 1500 RPM to facilitate extraction
For 10 minutes, then drop to 500 RPM. The suspension thus obtained is kept stirred and pumped with a screw pump through a squeeze filter set at 1 atmospheric pressure. When this filtration is complete, the product is "dry"
And through a filter of n-hexane, a solvent that has a dual activity of dissolving any remaining surfactant that may be present on the surface of the microspheres. The product is then placed in a suitable container and stored at 4 ° C. The average particle size is 10 μm. The molecular weight of the polymers that make up the microspheres is approximately 500,000-8.
It is 00000.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Lanfranco Carregallo Italy 35020 Padova, Ponte di Branta, Via Brabi No. 35

Claims (51)

[Claims] 1. Total and partial esters of gellan esterified with aliphatic, arylaliphatic, alicyclic or heterocyclic alcohols and salts of these partial esters with inorganic or organic bases. 2. The alcohol component is unsubstituted or amino having 1 to 34 carbon atoms, hydrocarbylamino, dihydrocarbylamino, hydroxyl or ether thereof; mercapto or thioether or thioester thereof; formyl, keto, carboxyl or ester thereof. ; Acetal, ketal, alkoxy,
Carbamidic, and 1 having 1 to 6 carbon atoms
Or an aliphatic alcohol substituted with 1 or 2 functional groups selected from the group consisting of carbamidic groups substituted with 2 alkyl groups, which is a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen The ester of gellan and a salt thereof according to claim 1, which is derived from an aliphatic alcohol whose carbon atom chain may be blocked by. 3. The aliphatic alcohol component is selected from the group consisting of carbamidic, amino, ether, ester, thioether, thioester, acetal, ketal or a hydrocarbylamino group containing an alkyl group having 1 to 4 carbon atoms. Derived from an alcohol having 1 to 12 carbon atoms which may be substituted with a functional group, wherein the hydrocarbyl group in the esterified carboxyl group and the substituted carbamidic group is an alkyl having the same number of carbon atoms. The ester of gellan and salts thereof according to claim 2, which is a group and the substituted amino or carbamidic group can also be an alkyleneamino or alkylenecarbamidic group having up to 8 carbon atoms. 4. The alcohol component for esterification comprises:
Esters of gellan and salts thereof according to claim 3, derived from ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amyl, pentyl, hexyl or octyl alcohol. 5. The alcohol component for esterification comprises:
The ester of gellan and a salt thereof according to claim 3, which is derived from glycerin. 6. The alcohol component for esterification comprises:
The ester of gellan and a salt thereof according to claim 3, which is derived from tartron alcohol, lactic acid, glycolic acid, malic acid, tartaric acid or citric acid. 7. The alcohol component for esterification comprises:
Aminoethanol, aminopropanol, n-aminobutanol or its N, N-dimethyl or N, N-diethyl derivative; choline, pyrrolidinyl ethanol, piperidinyl ethanol, piperazinyl ethanol or the corresponding n-propyl alcohol or n An ester of gellan and a salt thereof according to claim 3, which is derived from a derivative of butyl alcohol, a monothioethylene glycol or a lower alkylmercapto derivative. 8. The alcohol component for esterification comprises:
The ester of gellan and a salt thereof according to claim 1, which is derived from a higher aliphatic alcohol selected from the group consisting of cetyl alcohol, myricyl alcohol, citronellol, geraniol, nerol, nerolidol, linalool, farnesol and phytol. 9. The alcohol component for esterification comprises:
An arylaliphatic alcohol having one benzene residue and an aliphatic chain of 1 to 4 carbon atoms, wherein the benzene residue is 1-3 selected from the group consisting of methyl, methoxy, hydroxy and halogen atoms. Aryl whose aliphatic chain is optionally substituted with 1 or 2 groups selected from the group consisting of free, mono- or diethylated amino groups, pyrrolidine and piperidine groups. The gellan ester and its salt according to claim 1, which are derived from an aliphatic alcohol. 10. The alcohol is benzyl alcohol,
The ester of gellan and a salt thereof according to claim 9, which is selected from the group consisting of phenethyl alcohol, ephedrine and adrenaline. 11. A cycloaliphatic, aliphatic-cycloaliphatic or heterocyclic alcohol is unsubstituted or amino having from 3 to 34 carbon atoms, hydrocarbylamino, dihydrocarbylamino, hydroxyl or ether thereof; mercapto or Thioether or thioester thereof; formyl, keto, carboxyl or ester thereof; acetal, ketal, alkoxy, carbamidic, and carbamidic group substituted with 1 or 2 alkyl groups having 1 to 6 carbon atoms A monocyclic or polycyclic hydrocarbon substituted with one or more functional groups, wherein -O-, = N-, -NH
A carbon atom chain may be interrupted by a heteroatom selected from the group consisting of -or -S-, and may have one or more double bonds. The ester of gellan and a salt thereof according to claim 1, which is derived from a cyclic hydrocarbon. 12. The alcohol is a monocyclic hydrocarbon having 3 to 12 carbon atoms, the ring having 5 to 7 carbon atoms and substituted with 1 to 3 lower alkyl groups. The gellan ester and its salt according to claim 11, which may be present. 13. The alcohol is cyclohexanol,
Cyclohexanediol, cyclohexane-1,2,3-
Triol, cyclohexane-1,3,5-triol,
Inositol, carbomenthol, γ-menthol, α
And γ-terpineol, terpineol-1, terpineol-4, piperitol, 1,4- and 1,8-
The ester of gellan and a salt thereof according to claim 12, which is selected from the group consisting of terpines. 14. The alcohol is tujanol, sabinol, pinol hydrate, D- or L-borneol,
And D- or L-isoborneol.
The ester of gellan according to 2 and a salt thereof. 15. The polycyclic alcohol is sterins, cholic acids or steroid alcohols.
The ester of gellan according to 1 and a salt thereof. 16. The alcohol is selected from the group consisting of cholesterol, dihydrocholesterol, epidihydrocholesterol, coprosterol, epicoprosterol, sitosterol, stigmasterol, ergosterol, cholic acid, desoxycholic acid and lithocholic acid. Item 15. The ester of gellan and a salt thereof according to Item 15. 17. The ester of gellan according to claim 15, wherein the alcohol is selected from the group consisting of estrone, estradiol, estratriol, equilenin, equilin, and its 7-position methyl derivative and its 17-position ethynyl or propynyl derivative. And its salt. 18. The alcohol is pregnenolone, pregnanediol, testosterone, 17-methyltestosterone, 1,2-dihydrotestosterone, 17-methyl-1,2-dihydrotestosterone, 17-ethynyltestosterone, 17-propynyltestosterone,
The gellan ester and its salt according to claim 15, which is selected from the group consisting of norgestrel, hydroxyprogesterone, 19-nortestosterone, 19-nor-17-methyltestosterone and 19-nor-17-ethynyltestosterone. 19. The alcohol is cortisone, hydrocortisone, prednisone, prednisolone, fludrocortisone, dexamethasone, betamethasone, corticosterone, desoxycorticosterone, parameterzone,
The ester of gellan and a salt thereof according to claim 15, which is selected from the group consisting of flumethasone, fluocinolone and fluocinolone acetonide, flupredonelidene, clobetasol and beclomethasone. 20. The ester of gellan and a salt thereof according to claim 15, wherein the alcohol is selected from the group consisting of the cardioactive glycosides genins. 21. The alcohols are acceloftol, calciferol and vitamins D2, D3 and D4.
The ester of gellan and a salt thereof according to claim 1, which is selected from the group consisting of: 22. The ester of gellan and a salt thereof according to claim 11, wherein the alcohol is selected from the group consisting of anoylin, lactoflavin, ascorbic acid, riboflavin, thiamine and pantothenic acid. 23. Alcohol, alkaloids, phenylethylamines, phenothiazines, thioxanthenes, anticonvulsants, antipsychotics, antiemetics, analgesics, hypnotics, appetite suppressants, tranquilizers, Muscle relaxants, coronary vasodilators, adrenergic blockers, anesthetic antagonists, anti-neoplastic drugs, antibiotics, antiviral drugs, peripheral vasodilators, carbonic anhydrase inhibitors, anti-asthma drugs, anti-inflammatory drugs and The ester of gellan and a salt thereof according to claim 11, which is selected from the group consisting of sulfamide drugs. 24. The ester of gellan according to claim 1, wherein all carboxy groups of gellan are esterified. 25. The ester of gellan and a salt thereof according to claim 1, wherein at least 5% and at most 95% of all carboxy groups of gellan are esterified. 26. The ester of gellan and a salt thereof according to claim 1, wherein the carboxy group of gellan is esterified with a different alcohol. 27. The ester of gellan and its salt according to claim 26, wherein the two different alcohols are esterified and the ratio of the numbers of the two different alcohols is changed from 1:10 to 10: 1. . 28. A gellan salt according to claim 1, derived from an alkali metal, alkaline earth metal, ammonium or aluminum. 29. The salt of claim 28 which is the sodium or ammonium salt of gellan. 30. A partial ester salt according to claim 1, derived from an aliphatic, arylaliphatic, alicyclic or heterocyclic amine base. 31. The partial ester salt according to claim 30, wherein the amine base is a therapeutically acceptable base. 32. An amine base is an alkaloid, peptide, phenothiazine, benzodiazepine, thioxanthene, hormone, vitamin, anticonvulsant, antipsychotic drug,
Anti-emetics, anesthetics, hypnotics, appetite suppressants, tranquilizers,
Muscle relaxants, coronary vasodilators, anti-neoplastic agents, antibiotics,
Antibacterial agents, antiviral agents, antimalarial agents, carbonic anhydrase inhibitors, non-steroidal anti-inflammatory agents, vasoconstrictors, cholinergic agonists, cholinergic antagonists, adrenergic agonists, adrenergic blockers and anesthesia 32. The partial ester salt according to claim 31, which is selected from the group consisting of drug antagonists. 33. The amine is pharmacologically inactive, 1
Mono-, di-, and trialkylamines having 8 carbon atoms; methyl, halogen atoms, hydroxyl groups, O
And substituted by 1 to 3 substituents selected from the group consisting of alkyleneamine groups having a ring of 4 to 6 carbon atoms, which may be blocked by heteroatoms selected from the group consisting of Selected from the group consisting of an arylalkylamine having a benzene ring as the aromatic moiety, which is also optionally present, and having 1 to 8 carbon atoms in the cycloaliphatic moiety; and amines substituted with amino or hydroxyl groups. Item 32. A partial ester salt according to Item 31. 34. The salified group is a quaternary tetraalkylammonium group derived from any of the amines of claim 33, wherein the fourth alkyl group has 1 to 4 carbon atoms. 32. The partial ester salt according to claim 31. 35. A pharmaceutical preparation comprising as active ingredient an effective amount of any of the gellan esters or salts thereof according to claim 1 together with a pharmaceutically acceptable excipient. 36. (1) An effective amount of a pharmacologically active substance;
And (2) a carrier comprising the whole or partial ester of gellan or a salt thereof according to claim 1, or a pharmaceutical preparation or a medicament. 37. At least one ester group or 1
A pharmaceutical preparation comprising an effective amount of gellan ester according to claim 1 and a pharmaceutically acceptable carrier, wherein each of the salified carboxy groups of the species is derived from a therapeutically active alcohol or base. Or medicine. 38. The pharmaceutical preparation or medicament according to claim 35 or 36 for use in ophthalmology, dermatology, otolaryngology, dentistry, angiography, obstetrics or neurology. 39. A cosmetic product comprising either the ester of gellan according to claim 1 or a salt thereof. 40. A hygiene or surgical article comprising any of the ester of gellan according to claim 1 or a salt thereof. 41. The hygiene or surgical article of claim 40 in the form of a gellan ester film. 42. The sanitary or surgical article according to claim 40, which is in the form of a thread. 43. A gellan ester is dissolved in a first organic solvent, the solutions are each wrapped or spun, and treatment with a second suitable organic or aqueous solvent in which the first solvent is soluble and the gellan ester is insoluble. 40. The method for producing a gellan ester film or thread according to claim 39, wherein the organic solvent is removed by to produce a film or thread. 44. The method of claim 43, wherein dimethyl sulfoxide is used as the first solvent. 45. A gellan ester according to claim 1
Food containing seeds or more. 46. Articles for use in the textile, printing and paper industry containing at least one gellan ester according to claim 1. 47. A gellan ester according to claim 1
Household products or cleaners containing seeds or higher. 48. An emulsifier containing one or more gellan esters or salts thereof according to claim 1. 49. A method comprising treating a quaternary ammonium salt of gellan with an esterifying agent in an aprotic solvent, optionally salifying the free carboxy groups in the resulting ester containing carboxy groups. 1. The method for producing gellan ester according to 1. 50. The method according to claim 49, wherein dimethyl sulfoxide is used as the aprotic solvent. 51. A quaternary ammonium salt of gellan is produced by using a lower tetraalkylammonium salt.
The method according to item 9.